Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents.
| Title: | Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents. |
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| Authors: | Piccolo M; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Russo C; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Arciuolo V; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Ferraro MG; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via Pansini 5, Naples 80131, Italy.; Abbate V; Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street London SE1 9NH, United Kingdom of Great Britain and Northern Ireland.; Di Porzio A; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Cinquegrana E; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Di Leva FS; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Pagano B; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Randazzo A; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Hider RC; Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street London SE1 9NH, United Kingdom of Great Britain and Northern Ireland.; Irace C; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Amato J; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy.; Giustiniano M; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples 80131, Italy. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2025 Jan 23; Vol. 68 (2), pp. 1245-1259. Date of Electronic Publication: 2025 Jan 01. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | G-Quadruplexes*/drug effects ; Iron Chelating Agents*/pharmacology ; Iron Chelating Agents*/chemical synthesis ; Iron Chelating Agents*/chemistry ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemical synthesis ; Antineoplastic Agents*/chemistry ; Drug Design*; Cell Proliferation/drug effects ; Iron/metabolism ; Iron/chemistry ; Humans ; Jurkat Cells ; Structure-Activity Relationship ; Drug Screening Assays, Antitumor ; Drug Synergism ; Molecular Structure |
| Abstract: | Iron homeostasis is strictly related to numerous physiological pathways including cell cycle progression and cell growth. The newest anticancer strategies focus on either depleting the cells with a suitable chelator or increasing their loading by administering iron complexes to induce ferroptosis. Iron depletion inhibits cell proliferation, while iron overload induces the damage of guanine nucleobases in G-quadruplex structures via ROS generation, leading to genome instability. Here, we demonstrated that designing a molecular chimera embodying structural requirements for both iron chelation and G-quadruplex binding can result in dual-targeting compounds endowed with synergistic anticancer effects. We designed, synthesized, and tested a library of such compounds through biophysical and biological experiments. Compound 16 emerged as a lead candidate and a pharmacological tool able to chelate iron and stabilize G-quadruplexes in human leukemia Jurkat cells. Notably, it also localizes in the cell nucleus, serving as an intrinsically fluorescent nuclear tracer for the labile iron pool. |
| Substance Nomenclature: | 0 (Iron Chelating Agents); 0 (Antineoplastic Agents); E1UOL152H7 (Iron) |
| Entry Date(s): | Date Created: 20250101 Date Completed: 20250123 Latest Revision: 20250319 |
| Update Code: | 20260130 |
| DOI: | 10.1021/acs.jmedchem.4c01665 |
| PMID: | 39743313 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't